Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels-Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and <i>N</i>-substituted maleimides, to afford a series of 9-(<i>E</i>)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(<i>E</i>)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes <b>23f</b>, <b>23h</b>, <b>24a</b>, <b>24g</b>, <b>25f</b> and <b>27</b>. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as <b>20a</b>, <b>20f, 23a</b> and <b>25n</b> with IC₅₀ values in the ranges of 0.17-2.69 µM (HG-3) and 0.35-1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds <b>20a</b>, <b>20f, 23a</b> and <b>25n</b> were demonstrated in CLL cell lines HG-3 (82-95%) and PGA-1 (87-97%) at 10 µM, with low toxicity (12-16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC₅₀ values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, <b>20a</b>, <b>20f, 23a</b> and <b>25n,</b> was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. <b>25n</b> also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI₅₀ value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.